DESCRIPTION: (Applicant's Abstract) The applicant is director of the Drug Abuse Program, started in 1997 at the Research Institute Neurosciences of the Free University in Amsterdam. This multidisciplinary research program currently evaluates the hypothesis that self-administration of addictive drugs may cause similar long-lasting neuroadaptive changes in the mesocorticolimbic system, resulting in a persistent hyper-responsiveness towards these drugs, environmental factors (cue's) and stressors and consequently in an enduring addiction prone state. This hypothesis is tested in rats and mice. The major aim of this research program is to define new pharmacotherapeutic targets in the brain of addicts and to provide the scientific basis for successful clinical trials. Our behavioural studies include analysis of acquisition of (intravenous) heroin, psychostimulant and (oral) ethanol self-administration as well as the reinstatement of (non-reinforced) drug-seeking behavior. Temporal changes in signal transduction processes are studied neurochemically and electrophysiologically in brain slices. Mesolimbic gene expression patterns are studied using differential display PCR, subtractive hybridization, cDNA microarrays and quantitative in situ hybridization histochemistry. Neuropeptide and protein synthesis is investigated by means of mass spectroscopy and nano-scale separation and detection techniques. Protein phosphorylation is studied using two-dimensional gel electrophoresis. Moreover, pharmacological (receptor (ant)agonists) and molecular biological (anti-sense and retroviral vector techniques, transgenic mice, inducible knockouts) interventions are used to reveal the causal relationships between addiction behavior and adaptive changes in neuronal communication.